JP2007185494A - Amphiphilic copolymer composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an amphiphilic copolymer composition, an amphiphilic coating material for applying on at least a portion of one surface of an article, and an article having an amphiphilic coating film. <P>SOLUTION: This amphiphilic coating material includes a copolymer containing one or more alkyl methacrylate or alkyl acrylate co-monomer units, one or more vinyl acetate co-monomer units, and up to 40 mol% of polyethylene oxide substituted methacrylate co-monomer units. Optionally, one or more biologically active molecules may be covalently bonded to the polyethylene oxide substituted methacrylate co-monomer units. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

Disclosure details

(Field of the Invention)
The present invention relates to an amphiphilic coating material for delivery over at least a portion of one surface of an article. The present invention also relates to an article having an amphiphilic coating according to the present invention.

BACKGROUND OF THE INVENTION
Most medical devices are made of metal, ceramic, or polymeric materials. However, these materials are hydrophobic, non-conformal, and non-slippery, which can cause thrombus formation, inflammation, or other injury to the mucosa during use or operation. May cause. This biocompatibility issue is therefore an important issue for manufacturers of medical devices, particularly medical implants. In order to function properly and safely, medical devices are typically coated with one or more layers of biocompatible material. The coatings on these medical devices can also be used in some cases to deliver therapeutic or pharmaceutical substances.

  Medical devices, particularly implantable medical devices, are intended for long-term use and are directly interrelated to body tissues, fluids, electrolytes, proteins, enzymes, lipids, and other biological molecules. In order to work, the coating materials for these medical devices must meet stringent biological and physical requirements. These requirements are, at a minimum, the following conditions: (1) The coating must be hydrophilic and lubricious when in contact with body tissue, thereby improving patient comfort during surgery. Enhancing and improving the operability of the medical device, (2) the coatings need to be flexible and elastic, so that these coatings are biological structures without inducing harmful stress (3) the coating must be blood compatible, thereby reducing or avoiding the formation of thrombi or emboli, and (4) the coating is chemically sensitive to body tissues and fluids. And (5) the coating must be mechanically durable and not cracked when formed on a medical device. In addition, if the above-described coating is impregnated with a pharmaceutical or therapeutic substance, the coating and the formation thereof must be compatible with the pharmaceutical or therapeutic substance. Is generally required. In addition, if the above-described coating is used as a coating material and the underlying underlying coating is impregnated with a pharmaceutical or therapeutic substance, the coating and its formation are impregnated in the underlying coating. Must be compatible with the medicinal or therapeutic substance, and the coating must allow the medicinal or therapeutic substance to penetrate the coating, That is also needed. The coating may also function as a physical barrier, a chemical barrier, or a combination thereof to regulate the dissolution of a pharmaceutical or therapeutic substance in the underlying base coating. desirable.

  In order to combine the desired properties of different polymeric materials, conventional coating compositions for commercially available drug eluting stents are polymer blends of polyethylene-vinyl acetate (EVAc) and polybutyl methacrylate (BMA), ie , A physical mixture. However, a disadvantage of this conventional coating is the phase separation of the polymer mixture, which can be detrimental to the performance of the coating and the stability of the drug impregnated therein. is there.

  Another coating composition of the prior art includes a supporting polymer and a hydrophilic polymer, where the supporting polymer comprises a functional moiety capable of causing a crosslinking reaction. Including, the hydrophilic polymer is attached to a supporting polymer (see, eg, US Pat. No. 6,238,799). However, the preparation of this prior art coating composition uses a chemical cross-linking reaction and a high temperature curing process, which are not compatible with drug-containing coatings.

  The prior art also uses coating compositions formed by the gas phase or plasma polymerization of a gas containing monomers of polyethylene glycol vinyl ether compounds (eg, US 2003/0113477). No.) However, polymers prepared by such plasma treatment have poorly defined molecular weight and large polydispersity. Furthermore, low molecular weight plasma polymerized polymers have limited mechanical durability. Also, such plasma treatment can penetrate into the underlying underlying coating and damage the drug-containing material therein. Furthermore, another problem with this prior art method is that free radicals or other high energy species generated during this plasma treatment remain in the coating, and over time the drug in the base coating It can cause loss of inclusions.

  In order to reduce thrombosis caused by the use of medical devices, the prior art improves the coating of medical devices by conjugating, i.e. covalently binding, an antithrombotic substance to the coating ( See, for example, US Pat. No. 4,973,493 and www.surmodics.com). While this method can produce coatings with superior antithrombogenic properties, this prior art conjugate method uses UV irradiation treatment and / or chemical cross-linking treatment, and these The treatment can cause degradation of the antithrombotic material in the coating.

  Thus, a sensitive pharmaceutical or treatment impregnated in a coating material that can meet the stringent requirements, as described above, for delivery to at least one surface of a medical device There remains a need for coating materials that can be prepared by methods that are compatible with the materials used.

[Summary of the Invention]
Accordingly, the present invention provides an amphiphilic coating material for delivery over at least a portion of one surface of an article. This “amphiphilic” means having hydrophobic and hydrophilic properties at the same time. Such amphiphilic coating materials include one or more alkyl methacrylate or alkyl acrylate comonomer units, one or more vinyl acetate comonomer units, and up to 40 mole percent polyethylene oxide substituted methacrylate. And a co-monomer unit. Optionally, one or more biologically active molecules may be covalently bonded to the above-described polyethylene oxide substituted methacrylate comonomer units.

この場合に、
Ｒは、水素原子、１〜６個の炭素原子のアルキル基、または生物学的に活性な分子、であり、
ｎは２〜１００の整数であり、
ｍは１００〜５０００の整数である。 Preferably, the comonomer unit of the above polyethylene oxide-substituted methacrylate comprises the following structure:

In this case,
R is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a biologically active molecule,
n is an integer from 2 to 100;
m is an integer of 100 to 5000.

  The present invention also provides an article having an amphiphilic coating on the surface. The amphiphilic coating material comprises one or more alkyl methacrylate or alkyl acrylate comonomer units, one or more vinyl acetate comonomer units, and up to 40 mol% polyethylene oxide substituted methacrylate comonomer. And a copolymer containing the unit. Optionally, one or more biologically active molecules may be covalently bonded to the above-described polyethylene oxide substituted methacrylate comonomer units. Preferably, the article is a medical device or a component of a medical device.

Detailed Description of the Invention
The present invention provides an amphiphilic coating material for delivery over at least a portion of one surface of an article. The amphiphilic coating material comprises one or more alkyl methacrylate or alkyl acrylate comonomer units, one or more vinyl acetate comonomer units, and up to 40 mol% polyethylene oxide substituted methacrylate comonomer. And a copolymer containing the unit. The comonomers in the copolymer, i.e., alkyl methacrylate or alkyl acrylate comonomers, vinyl acetate comonomers, and polyethylene oxide substituted methacrylate comonomers, are in a random sequence. “Alkyl methacrylate” means a derivative of methacrylate. In this case, the oxygen atom bonded to the carbon atom of the carbonyl group is substituted with an alkyl group. “Alkyl acrylate” means a derivative of acrylate. In this case, the oxygen atom bonded to the carbon atom of the carbonyl group is substituted with an alkyl group. “Polyethylene oxide-substituted methacrylate” means a derivative of methacrylate, and in this case, the oxygen atom bonded to the carbon atom of the carbonyl group is substituted with a polyethylene oxide moiety.

  The copolymer has a hydrophobic main chain formed by polymerization of vinyl groups. In addition, the polyethylene oxide portion of the polyethylene oxide-substituted methacrylate comonomer provides a hydrophilic pendent chain interspersed with the hydrophobic main chain. Yes. In addition, the polyethylene oxide moiety in the polyethylene oxide substituted methacrylate comonomer also provides a functional group to which one or more biologically active molecules can be attached. This “biologically active molecule”, as used herein, refers to a compound or substance that affects or elicits a response from living tissue. Such biologically active molecules bind to the polyethylene oxide moiety by forming a covalent bond to the oxygen atom at the far end position of the polyethylene oxide moiety. The “oxygen atom at the far end” means the oxygen atom of the polyethylene oxide portion that is farthest from the carbonyl group in the polyethylene oxide-substituted methacrylate. This causes the hydrophilic pendant chains in the copolymer to swell under physiological conditions to form a flexible and lubricious three-dimensional network structure, thereby binding biologically active molecules. It is possible to provide a hydrophilic environment for maintaining the optimal activity.

この場合に、
Ｒは、水素原子、１〜６個の炭素原子を有するアルキル基、または生物学的に活性な分子、であり、
ｎは２〜１００の整数であり、
ｍは１００〜５０００の整数である。
好ましくは、ｎは２〜１０の整数である。また、本発明に適しているアルキル基は、直鎖状、分枝状、または環状、であってよい。適当なアルキル基の例は、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｔｅｒｔ−ブチル、ｎ−ペンチル、シクロプロピル、シクロブチル、およびシクロペンチル、を含むが、これらに限定されない。好ましくは、上記アルキル基はメチルである。 Preferably, the comonomer unit of the polyethylene oxide-substituted methacrylate has the following structure:

In this case,
R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a biologically active molecule,
n is an integer from 2 to 100;
m is an integer of 100 to 5000.
Preferably, n is an integer of 2-10. Also, alkyl groups suitable for the present invention may be linear, branched, or cyclic. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, and cyclopentyl. Preferably, the alkyl group is methyl.

  The biologically active molecule is covalently attached to the polyethylene oxide moiety by a conjugation process. This conjugation process includes one or more chemical or light irradiation reactions. Biologically active molecules suitable for the present invention have a therapeutic effect, for example to treat or prevent a biological organism's response to disease or introduction of the medical device into the organism, Any drug, agent, formulation and / or combination thereof is included. Preferred biologically active molecules are anti-thrombogenic agents, immunosuppressants, antitumor agents, anti-inflammatory agents, angiogenesis inhibitors, protein kinase inhibitors, and treat and reduce restenosis in mammals, Or other agents that can be prevented, but are not limited thereto. Furthermore, examples of biologically active molecules of the present invention include heparin, albumin, streptokinase, tissue plasminogin activator (TPA), urokinase, rapamycin, paclitaxel, pimecrolimus. , And analogs and derivatives thereof, but are not limited to these. In addition, when the copolymer includes two or more types of biologically active molecules, these biologically active molecules may be the same or different.

この場合に、Ｒ¹ は１〜１２個の炭素原子を有するアルキル基である。このアルキル基は、直鎖状、分枝状、または環状、であってよい。適当なアルキル基の例は、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｔｅｒｔ−ブチル、ｎ−ペンチル、シクロプロピル、シクロブチル、およびシクロペンチル、を含むが、これらに限定されない。好ましくは、上記のアルキル基はメチルまたはブチルである。 Preferably, the alkyl methacrylate comonomer unit has the general formula:

In this case, R ¹ is an alkyl group having ¹ to 12 carbon atoms. The alkyl group can be linear, branched, or cyclic. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, and cyclopentyl. Preferably, the alkyl group is methyl or butyl.

この場合に、Ｒ² は１〜１２個の炭素原子を有するアルキル基である。このアルキル基は、直鎖状、分枝状、または環状、であってよい。適当なアルキル基の例は、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｔｅｒｔ−ブチル、ｎ−ペンチル、シクロプロピル、シクロブチル、およびシクロペンチル、を含むが、これらに限定されない。好ましくは、上記のアルキル基はメチルまたはブチルである。 Preferably, the alkyl acrylate comonomer unit has the general formula:

In this case, R ² is an alkyl group having 1 to 12 carbon atoms. The alkyl group can be linear, branched, or cyclic. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, and cyclopentyl. Preferably, the alkyl group is methyl or butyl.

  Further, when the copolymer includes two or more types of alkyl methacrylate or alkyl acrylate comonomers, these two or more types of methacrylate or acrylate comonomers may be the same or different. Preferred alkyl methacrylate comonomers include methyl methacrylate, ethyl methacrylate, butyl methacrylate, and cyclic alkyl methacrylate. Preferred alkyl acrylate comonomers also include methyl acrylate, ethyl acrylate, butyl acrylate, and cyclic alkyl acrylate. It is understood by those skilled in the art that suitable alkyl methacrylate or acrylate comonomers also include any similar alkyl methacrylate or alkyl acrylate of the above alkyl methacrylate and alkyl acrylate comonomers. Is done.

この場合に、
Ｒ³ は１〜６個の炭素原子を有するアルキル基であり、
Ｒ⁴ は水素原子または１〜６個の炭素原子を有するアルキル基である。
本発明に適しているアルキル基は、直鎖状、分枝状、または環状、であってよい。本発明の一例の好ましい実施形態において、上記ビニル・アセテートのコモノマーは、Ｒ³ がメチルであって、Ｒ⁴ が水素である、化学式（ＩＶ）の構造を有する化合物である。なお、当業界の熟練者において、適当なビニル・アセテートのコモノマーは、上記のビニル・アセテートのコモノマーのあらゆる類似のビニル・アセテートも含むことが理解される。 Preferably, the vinyl acetate monomer has the general formula:

In this case,
R ³ is an alkyl group having 1 to 6 carbon atoms,
R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
Alkyl groups suitable for the present invention may be linear, branched, or cyclic. In one preferred embodiment of the present invention, the vinyl acetate comonomer is a compound having the structure of formula (IV), wherein R ³ is methyl and R ⁴ is hydrogen. It will be understood by those skilled in the art that suitable vinyl acetate comonomers include any similar vinyl acetate of the above-mentioned vinyl acetate comonomers.

この場合に、
Ｒ⁵ は１〜１２個の炭素原子を有するアルキル基であり、
Ｒ⁶ は水素原子または１〜６個の炭素原子を有するアルキル基であり、
ｎは２〜１００の整数であり、
ｘ、ｙおよびｚは、同一であるか異なっていて、独立して、１０〜２５００の整数である。
好ましくは、ｎは２〜１０の整数である。 In an exemplary embodiment of the invention, the copolymer comprises the following repeating units:

In this case,
R ⁵ is an alkyl group having 1 to 12 carbon atoms,
R ⁶ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
n is an integer from 2 to 100;
x, y and z are the same or different and are independently integers of 10 to 2500.
Preferably, n is an integer of 2-10.

この場合に、
Ｒ⁷ は１〜１２個の炭素のアルキル基であり、
ｎは２〜１００の整数であり、
ｘ、ｙおよびｚは、同一であるか異なっていて、独立して、１０〜２５００の整数である。
好ましくは、ｎは２〜１０の整数である。ヘパリンは、血液の凝固能力を低下させて、血管の中に有害な血餅が形成するのを防ぐために用いられる、周知の抗血液凝固薬である。上記のポリエチレン・オキシドの部分へのヘパリンの結合は、その結果として得られるコポリマーが塗布処理において用いられる一般的な有機溶媒に可溶性になることを可能にし、これにより、水の使用を排除して、被膜の形態学的な性質を改善する。上記化学式（ＶＩ）のコポリマーを含有している被膜は高められた血液適合性を有しており、したがって、植え込み可能な医療装置のための被膜として、特に有用である。 In an exemplary embodiment of the invention, the copolymer comprises the following repeating units:

In this case,
R ⁷ is an alkyl group of 1 to 12 carbons;
n is an integer from 2 to 100;
x, y and z are the same or different and are independently integers of 10 to 2500.
Preferably, n is an integer of 2-10. Heparin is a well-known anticoagulant used to reduce the ability of blood to clot and prevent the formation of harmful clots in blood vessels. The binding of heparin to the above polyethylene oxide moiety allows the resulting copolymer to become soluble in common organic solvents used in the coating process, thereby eliminating the use of water. Improve the morphological properties of the coating. Coatings containing the above formula (VI) copolymer have enhanced blood compatibility and are therefore particularly useful as coatings for implantable medical devices.

The copolymers in accordance with the present invention provide from about 10 K to about 5000 K Daltons (from about 1.66 × 10 ⁻²⁰ g to about 8.30) to allow the formation of polymers with desirable mechanical durability and adequate adhesion. Preferably, it has a tunable polymer molecular weight in the range of ^{x10 -18} g). Since the mechanical durability of the coating is improved with increasing molecular weight of the polymer, the copolymers of the present invention are coatings for certain medical devices (eg, stents) that need to be expanded and deployed in vivo. It is particularly preferred to have a high polymer molecular weight of from 50 K to 5000 K Dalton (8.30 × 10 ⁻²⁰ g to 8.30 × 10 ⁻¹⁸ g).

  The amphiphilic coatings of the present invention are co-solvents such as plasticizers, antifoaming agents, anticrater agents, and coalescing solvents to facilitate high quality film formation. And / or other additives. Other suitable additives to such amphiphilic coating materials include bioactive agents, antibacterial agents, antithrombogenic agents, antibiotics, pigments, radiopacifiers and ionic conductors. However, it is not limited to these. Details regarding the selection and amounts of these ingredients are known to those skilled in the art.

The amphiphilic coating material according to the present invention can be applied to at least a portion of one surface of the article. In some embodiments, the coating of the present invention is applied to all exposed surfaces of the article. The thickness of the amphiphilic coating can be changed depending on the method used for forming the coating and the intended use of the article. Generally, in a medical device, the coating according to the present invention is provided in a thickness of about 10 × 10 ⁻¹⁰ to about 5000 × 10 ⁻¹⁰ m (about 10 to about 5000 cm), and about 20 × 10 ⁻¹⁰ to about Thicknesses of 1000 × 10 ⁻¹⁰ m (about 20 to about 1000 mm) are more common.

  When supplied to at least a portion of one surface of an article, the hydrophobic backbone of the copolymer according to the invention forms a non-swellable base layer and adheres to the underlying surface, The hydrophilic pendant chain hydrates and swells under physiological conditions to form a lubricious, blood compatible surface. The low friction and hemocompatibility of such hydrophilic pendant chains provide superior antithrombotic properties that potentially reduce subacute thrombosis (SAT). In addition, the hydrophobic backbone has a predetermined molecular weight with a narrow range of distribution that improves the mechanical durability of the polymer, while the hydrophilic pendant chain is It can be adjusted to various lengths to obtain the desired elasticity. Thus, the coatings according to the present invention are strong, i.e. mechanically durable and flexible, i.e. elastic. Such polymer robustness and flexibility in accordance with the present invention significantly reduces the peeling, delamination, and other defects commonly found in many current coatings on medical devices, particularly coatings on stents.

  Accordingly, the present invention provides an improved biocompatible coating that is sufficiently lubricious to reduce restenosis, or thrombosis, or other undesirable reactions, mammals Inactive hydrophilic surface for contacting the body tissue of an animal, for example a human, as well as enough to resist cracking when formed on an article, for example a medical device It also has a durable, hydrophobic main chain to adhere to the underlying surface.

  Amphiphilic coatings in accordance with the present invention can also be applied to tailor the dissolution of therapeutic dosages of drugs from a medical device base coating, eg, a stent base coating. The base coating generally comprises one or more drugs, agents, and / or compound substrates, and biocompatible materials such as polymers and the like. The above elution adjustment occurs as a result of either a physical barrier, or a chemical barrier, or a combination thereof. This elution is adjusted by changing the thickness of the coating, which can change the length of the diffusion path for drugs, agents and / or formulations to diffuse out of the base coating. In essence, drugs, agents and / or formulations in the base coating substrate diffuse through intervening spaces in the coating. Therefore, the thicker the coating, the longer the diffusion path, and conversely, the thinner the coating, the shorter the diffusion path. It is important to note that the basic coating and the thickness of the coating can be limited by the desired overall profile of the article to which they are applied.

  The properties of the copolymer according to the invention can be adjusted by adjusting the molar ratio of the comonomers. In other words, the molar ratio of the comonomer can be adjusted according to the desired properties of the copolymer according to the invention. For example, when a biologically active molecule is attached to the polyethylene oxide substituted methacrylate, the comonomer provides a hydrophilic environment to retain the optimal activity of the biologically active molecule. A molar ratio that ensures the desired mechanical strength of the copolymer. Preferably, the copolymer contains the alkyl methacrylate or alkyl acrylate, the vinyl acetate, and the polyethylene oxide substituted methacrylate, in a 1: 1: 1 molar ratio.

  The structure and molecular weight of the hydrophobic main chain of the polymer according to the present invention can be adjusted by employing various polymerization methods. Preferred polymerization methods of the present invention include group transfer polymerization (GTP), anionic polymerization, and living polymerization. A more preferred polymerization method of the present invention is GTP. This GTP is a living polymerization method including a Michael type addition reaction using a silyl ketene acetal initiator (for example, Vamvakari, M, et al., Polymer, 40, 1999, p. .5161-5171). Many conventional polymerization methods require chemical cross-linking reactions, high temperature curing treatments, and / or plasma treatments, which are very limited controls regarding the polymer backbone structure and molecular weight distribution. As well as causing drug damage in the underlying underlying coating. Unlike such conventional polymerization methods, GTP can be used for the synthesis of tailored acrylate or methacrylate polymers with a narrow molecular weight distribution at ambient temperature. The hydrophilic pendant chains of the copolymers according to the invention described above provide the desired lubricity and hemocompatibility, and the length of these hydrophilic pendant chains is the desired number of repeating ethylene. It can be controlled by using monomers with oxide units. Preferred monomers for this polymerization are those containing 2 to 10 repeating ethylene oxide units. In addition, these polyethylene oxide moieties serve as functional pendant chains so that one or more biologically active molecules are compatible with the biologically active molecule. It may be introduced by a conjugation process.

この場合に、
Ｒ⁵ は１〜１２個の炭素原子を有するアルキル基であり、
Ｒ⁶ は水素原子または１〜６個の炭素原子を有するアルキル基であり、
ｘ、ｙおよびｚは、独立して、１０〜２５００の整数であり、
ｎは２〜１００の整数である。
なお、上記の重合化処理において適当な触媒は当業界における熟練者において既知である。この触媒の例は、１−メトキシ−１−トリメチルシロキシ−２−メチル−１−プロペン（ＭＴＳ）、ｎ−テトラブチルアンモニウム・ビベンゾエート（n-tetrabutylammonium bibenzoate）（ＴＢＡＢＢ）、およびその他の重合開始剤、を含むが、これらに限定されない。 The general copolymerization of the present invention is shown in Equation 1 as follows:

In this case,
R ⁵ is an alkyl group having 1 to 12 carbon atoms,
R ⁶ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
x, y and z are each independently an integer of 10 to 2500;
n is an integer of 2 to 100.
Suitable catalysts for the above polymerization treatment are known to those skilled in the art. Examples of this catalyst are 1-methoxy-1-trimethylsiloxy-2-methyl-1-propene (MTS), n-tetrabutylammonium bibenzoate (TBABB), and other polymerization initiators. However, it is not limited to these.

この場合に、
Ｒ⁷ は１〜１２個の炭素原子を有するアルキル基であり、
ｘ、ｙおよびｚは、独立して、１０〜２５００の整数であり、
ｎは２〜１００の整数である。
上記の式２により示されている共役処理において、ポリエチレン・オキシドの部分は、ＤＭＡＰ（ジメチルアミノピリジン）の存在下で、その後ＤＣＣ（ジシクロヘキシルカルボジイミド）およびＮＨＳ（Ｎ−ヒドロキシル・スクシンイミド）の存在下で、クロロ酢酸により水酸基を処理することにより、活性化される。次に、ヘパリンが、その活性化されたポリエチレン・オキシドの部分により、共役処理される。このような、ヘパリンを誘導することによらない、コポリマーの段階的な活性化は、ヘパリンの誘導処理において一般的に見られる望ましくない架橋反応を最小限にするだけでなく、共役の程度に関して高度な制御を行なう。さらに、上記式２の共役処理は、穏やかな条件下に行なわれ、これにより、従来のＵＶ照射式の共役処理において発生される、望ましくない長期継続のフリーラジカル、を無くすことができる。 The general conjugation process of the present invention is shown in Equation 2 below.

In this case,
R ⁷ is an alkyl group having 1 to 12 carbon atoms,
x, y and z are each independently an integer of 10 to 2500;
n is an integer of 2 to 100.
In the conjugation process shown by equation 2 above, the polyethylene oxide moiety is in the presence of DMAP (dimethylaminopyridine) followed by DCC (dicyclohexylcarbodiimide) and NHS (N-hydroxyl succinimide). It is activated by treating the hydroxyl group with chloroacetic acid. The heparin is then conjugated with its activated polyethylene oxide moiety. Such stepwise activation of the copolymer, not by inducing heparin, not only minimizes undesirable cross-linking reactions commonly found in heparin derivation processes, but also has a high degree of conjugation. Control. Furthermore, the conjugation process of Formula 2 is performed under mild conditions, thereby eliminating the undesirable long-lasting free radicals that are generated in conventional UV irradiation type conjugation processes.

  The present invention also provides an article having on its surface an amphiphilic coating according to the present invention. The amphiphilic coating of the present invention is on at least a portion of one surface of the article. Such at least a portion of one surface of the article may be the surface of a polymer coating, a plastic material, ceramic, steel, or other alloy. Articles that can be coated with an amphiphilic coating material according to the present invention may be of any shape, and are preferably medical devices or parts of medical devices. The term “medical device”, as used herein, refers to a physical article that is used in a medical procedure, which includes an external medical device and an implantable medical device. Including both. Medical devices that can be coated with an amphiphilic coating material according to the present invention include catheters, guidewires, drug eluting stents, cochlear implants, retinal implants, gastric bands, nerve stimulation devices, muscle stimulation devices, implantable Including but not limited to drug delivery devices, intraocular devices, and various other medical devices.

  The amphiphilic coating material of the present invention can be applied to the surface of the article using conventional coating techniques such as spray coating, ultrasonic coating, dip coating, and the like. In the dip coating process, the article is taken out after being immersed in a bath containing an amphiphilic coating material. Residence times within the range of about 1 minute to about 2 hours can be used depending on the material of the structure, the complexity of the equipment, and the desired coating thickness. The article coated with the amphiphilic coating material can then be dried to form a dry coating. This drying may be accomplished simply by leaving at ambient conditions, and can be accelerated by heating at a moderate temperature, such as about 30 ° C. to about 65 ° C. .

  In the foregoing, the invention has been particularly illustrated and described with reference to preferred embodiments thereof, but it will be understood by those skilled in the art that these and other embodiments may vary in form. It will be. Furthermore, details thereof may be made without departing from the spirit and scope of the invention. Therefore, it is to be understood that the present invention is not limited to the precise forms described above and the details described and illustrated, but falls within the scope of the appended claims. Is intended.

この場合に、
Ｒは、水素原子、１〜６個の炭素原子のアルキル基、または、生物学的に活性な分子、であり、
ｎは、２〜１００の整数であり、
ｍは、１００〜５０００の整数である、
被膜材料。
（３）実施態様１に記載の被膜材料において、
前記ｎは、２〜１０である、被膜材料。
（４）実施態様１に記載の被膜材料において、
約１０×１０^-10〜約５０００×１０^-10ｍ（約１０〜約５０００Å）の厚さを有している、被膜材料。
（５）実施態様１に記載の被膜材料において、
前記コポリマーは、約１０Ｋ〜約５０００Ｋダルトン（約１．６６×１０^-20ｇ〜約８．３０×１０^-18ｇ）の範囲内の調整可能な分子量を有している、被膜材料。 Embodiment
(1) In an amphiphilic coating material for delivery over at least a portion of one surface of an article,
A copolymer comprising:
One or more alkyl methacrylate or alkyl acrylate comonomer units;
One or more types of vinyl acetate comonomer units, and
A comonomer unit of polyethylene oxide-substituted methacrylate up to 40 mol%,
Containing a copolymer,
A coating material comprising:
(2) In the coating material according to Embodiment 1,
The comonomer unit of the polyethylene oxide-substituted methacrylate includes the following structure:

In this case,
R is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a biologically active molecule,
n is an integer of 2 to 100,
m is an integer of 100 to 5000,
Coating material.
(3) In the coating material according to Embodiment 1,
N is 2 to 10;
(4) In the coating material according to embodiment 1,
A coating material having a thickness of about 10 × 10 ⁻¹⁰ to about 5000 × 10 ⁻¹⁰ m (about 10 to about 5000 mm).
(5) In the coating material according to embodiment 1,
The coating material, wherein the copolymer has a tunable molecular weight within the range of about 10K to about 5000K Daltons (about 1.66 × 10 ⁻²⁰ g to about 8.30 × 10 ⁻¹⁸ g).

この場合に、
Ｒ⁵ は、１〜１２個の炭素原子を有するアルキル基であり、
Ｒ⁶ は、水素原子、または、１〜６個の炭素原子を有するアルキル基、であり、
ｎは、２〜１００の整数であり、
ｘ、ｙおよびｚは、同一であるか異なっていて、独立して、１０〜２５００の整数である、
被膜材料。 (6) In the coating material according to embodiment 2,
The coating material, wherein the biologically active molecule is an antithrombogenic agent, an immunosuppressant, an antitumor agent, an anti-inflammatory agent, an angiogenesis inhibitor, or a protein kinase inhibitor.
(7) In the coating material according to embodiment 2,
The coating material wherein the biologically active molecule is selected from the group consisting of heparin, rapamycin, paclitaxel, pimecrolimus, and analogs and derivatives thereof.
(8) In the coating material according to embodiment 1,
The coating material, wherein the one or more methacrylate comonomers are selected from the group consisting of methyl methacrylate, ethyl methacrylate, butyl methacrylate, hexyl methacrylate, and octyl methacrylate.
(9) In the coating material according to embodiment 1,
The coating material, wherein the one or more acrylate comonomers are selected from the group consisting of methyl acrylate, ethyl acrylate, butyl acrylate, hexyl acrylate, and octyl acrylate.
(10) In the coating material according to embodiment 1,
The copolymer comprises the following repeating units:

In this case,
R ⁵ is an alkyl group having 1 to 12 carbon atoms,
R ⁶ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
n is an integer of 2 to 100,
x, y and z are the same or different and are each independently an integer from 10 to 2500;
Coating material.

この場合に、
Ｒ⁷ は、１〜１２個の炭素のアルキル基であり、
ｎは、２〜１００の整数であり、
ｘ、ｙおよびｚは、同一であるか異なっていて、独立して、１０〜２５００の整数である、
被膜材料。
（１２）物品の少なくとも一つの表面の上に供給するための、両親媒性の被膜材料において、
コポリマーであって、
１種類以上のアルキル・メタクリレートまたはアルキル・アクリレートのコモノマー単位、
１種類以上のビニル・アセテートのコモノマー単位、および、
４０モル％までのポリエチレン・オキシド置換型メタクリレートのコモノマー単位、
を含有している、コポリマー、
を含み、
１種類以上の生物学的に活性な分子が、前記ポリエチレン・オキシド置換型メタクリレートのコモノマー単位に、共有結合している、
被膜材料。
（１３）表面に両親媒性の被膜を有する物品において、
前記両親媒性の被膜は、コポリマーを含み、
前記コポリマーは、
１種類以上のアルキル・メタクリレートまたはアルキル・アクリレートのコモノマー単位、
１種類以上のビニル・アセテートのコモノマー単位、および、
４０モル％までのポリエチレン・オキシド置換型メタクリレートのコモノマー単位、
を含有している、
物品。
（１４）実施態様１３に記載の物品において、
前記ポリエチレン・オキシド置換型メタクリレートのコモノマー単位は、以下の構造を含んでおり、

この場合に、
Ｒは、水素原子、１〜６個の炭素原子のアルキル基、または、生物学的に活性な分子、であり、
ｎは、２〜１００の整数であり、
ｍは、１００〜５００の整数である、
物品。
（１５）実施態様１４に記載の物品において、
前記ｎは、２〜１０である、物品。 (11) In the coating material according to embodiment 1,
The copolymer comprises the following repeating units:

In this case,
R ⁷ is an alkyl group of 1 to 12 carbons;
n is an integer of 2 to 100,
x, y and z are the same or different and are each independently an integer from 10 to 2500;
Coating material.
(12) In an amphiphilic coating material for delivery on at least one surface of an article,
A copolymer comprising:
One or more alkyl methacrylate or alkyl acrylate comonomer units;
One or more types of vinyl acetate comonomer units, and
A comonomer unit of polyethylene oxide-substituted methacrylate up to 40 mol%,
Containing a copolymer,
Including
One or more biologically active molecules are covalently bound to the comonomer unit of the polyethylene oxide substituted methacrylate,
Coating material.
(13) In an article having an amphiphilic coating on the surface,
The amphiphilic coating comprises a copolymer;
The copolymer is
One or more alkyl methacrylate or alkyl acrylate comonomer units;
One or more types of vinyl acetate comonomer units, and
A comonomer unit of polyethylene oxide-substituted methacrylate up to 40 mol%,
Containing
Goods.
(14) In the article according to embodiment 13,
The comonomer unit of the polyethylene oxide-substituted methacrylate includes the following structure:

In this case,
R is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a biologically active molecule,
n is an integer of 2 to 100,
m is an integer of 100 to 500,
Goods.
(15) In the article according to embodiment 14,
The article, wherein n is 2-10.

この場合に、
Ｒ⁵ は、１〜１２個の炭素原子を有するアルキル基であり、
Ｒ⁶ は、水素原子、または、１〜６個の炭素原子を有するアルキル基、であり、
ｎは、２〜１００の整数であり、
ｘ、ｙおよびｚは、同一であるか異なっていて、独立して、１０〜５０００の整数である、
物品。 (16) In the article according to embodiment 14,
An article wherein the biologically active molecule is an antithrombogenic agent, an immunosuppressant, an antitumor agent, an anti-inflammatory agent, an angiogenesis inhibitor, or a protein kinase inhibitor.
(17) In the article according to embodiment 14,
An article wherein the biologically active molecule is selected from the group consisting of heparin, rapamycin, paclitaxel, pimecrolimus, and analogs and derivatives thereof.
(18) In the article according to embodiment 13,
The article, wherein the amphiphilic coating has a thickness of about 10 × 10 ⁻¹⁰ to about 5000 × 10 ⁻¹⁰ m (about 10 to about 5000 cm).
(19) In the article according to embodiment 13,
The article, wherein the copolymer has a tunable molecular weight in the range of about 10 K to about 500 K Daltons (about 1.66 × 10 ⁻²⁰ g to about 8.30 × 10 ⁻¹⁹ g).
(20) In the article according to embodiment 13,
The copolymer comprises the following repeating units:

In this case,
R ⁵ is an alkyl group having 1 to 12 carbon atoms,
R ⁶ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
n is an integer of 2 to 100,
x, y and z are the same or different and are independently integers of 10 to 5000;
Goods.

この場合に、
Ｒ⁷ は、水素原子、または、１〜６個の炭素のアルキル基、であり、
ｎは、２〜１００の整数であり、
ｘ、ｙおよびｚは、同一であるか異なっていて、独立して、１０〜２５００の整数である、
物品。
（２３）実施態様１３に記載の物品において、
医療装置、または、医療装置の部品、である、物品。 (21) In the article according to embodiment 13,
One or more biologically active molecules covalently bonded to the comonomer unit of the polyethylene oxide substituted methacrylate,
Further comprising an article.
(22) In the article according to embodiment 21,
The copolymer comprises the following repeating units:

In this case,
R ⁷ is a hydrogen atom or an alkyl group of 1 to 6 carbons,
n is an integer of 2 to 100,
x, y and z are the same or different and are each independently an integer from 10 to 2500;
Goods.
(23) In the article according to embodiment 13,
An article that is a medical device or a part of a medical device.

Claims (23)

In an amphiphilic coating material for delivery over at least a portion of one surface of an article,
A copolymer comprising:
One or more alkyl methacrylate or alkyl acrylate comonomer units;
One or more types of vinyl acetate comonomer units, and
A comonomer unit of polyethylene oxide-substituted methacrylate up to 40 mol%,
Containing a copolymer,
A coating material comprising: The coating material according to claim 1,
The comonomer unit of the polyethylene oxide-substituted methacrylate includes the following structure:

In this case,
R is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a biologically active molecule,
n is an integer of 2 to 100,
m is an integer of 100 to 5000,
Coating material. The coating material according to claim 1,
N is 2 to 10; The coating material according to claim 1,
A coating material having a thickness of about 10 × 10 ⁻¹⁰ to about 5000 × 10 ⁻¹⁰ m (about 10 to about 5000 mm). The coating material according to claim 1,
The coating material, wherein the copolymer has a tunable molecular weight within the range of about 10K to about 5000K Daltons (about 1.66 × 10 ⁻²⁰ g to about 8.30 × 10 ⁻¹⁸ g). The coating material according to claim 2,
The coating material, wherein the biologically active molecule is an antithrombogenic agent, an immunosuppressant, an antitumor agent, an anti-inflammatory agent, an angiogenesis inhibitor, or a protein kinase inhibitor. The coating material according to claim 2,
The coating material wherein the biologically active molecule is selected from the group consisting of heparin, rapamycin, paclitaxel, pimecrolimus, and analogs and derivatives thereof. The coating material according to claim 1,
The coating material, wherein the one or more methacrylate comonomers are selected from the group consisting of methyl methacrylate, ethyl methacrylate, butyl methacrylate, hexyl methacrylate, and octyl methacrylate. The coating material according to claim 1,
The coating material, wherein the one or more acrylate comonomers are selected from the group consisting of methyl acrylate, ethyl acrylate, butyl acrylate, hexyl acrylate, and octyl acrylate. The coating material according to claim 1,
The copolymer comprises the following repeating units:

In this case,
R ⁵ is an alkyl group having 1 to 12 carbon atoms,
R ⁶ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
n is an integer of 2 to 100,
x, y and z are the same or different and are each independently an integer from 10 to 2500;
Coating material. The coating material according to claim 1,
The copolymer comprises the following repeating units:

In this case,
R ⁷ is an alkyl group of 1 to 12 carbons;
n is an integer of 2 to 100,
x, y and z are the same or different and are each independently an integer from 10 to 2500;
Coating material. In an amphiphilic coating material for feeding on at least one surface of an article,
A copolymer comprising:
One or more alkyl methacrylate or alkyl acrylate comonomer units;
One or more types of vinyl acetate comonomer units, and
A comonomer unit of polyethylene oxide-substituted methacrylate up to 40 mol%,
Containing a copolymer,
Including
One or more biologically active molecules are covalently bound to the comonomer unit of the polyethylene oxide substituted methacrylate,
Coating material. In an article having an amphiphilic coating on the surface,
The amphiphilic coating comprises a copolymer;
The copolymer is
One or more alkyl methacrylate or alkyl acrylate comonomer units;
One or more types of vinyl acetate comonomer units, and
A comonomer unit of polyethylene oxide-substituted methacrylate up to 40 mol%,
Containing
Goods. The article of claim 13,
The comonomer unit of the polyethylene oxide-substituted methacrylate includes the following structure:

In this case,
R is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a biologically active molecule,
n is an integer of 2 to 100,
m is an integer of 100 to 500,
Goods. The article of claim 14, wherein
The article, wherein n is 2-10. The article of claim 14, wherein
An article wherein the biologically active molecule is an antithrombogenic agent, an immunosuppressant, an antitumor agent, an anti-inflammatory agent, an angiogenesis inhibitor, or a protein kinase inhibitor. The article of claim 14, wherein
An article wherein the biologically active molecule is selected from the group consisting of heparin, rapamycin, paclitaxel, pimecrolimus, and analogs and derivatives thereof. The article of claim 13,
The article, wherein the amphiphilic coating has a thickness of about 10 × 10 ⁻¹⁰ to about 5000 × 10 ⁻¹⁰ m (about 10 to about 5000 cm). The article of claim 13,
The article, wherein the copolymer has a tunable molecular weight in the range of about 10 K to about 500 K Daltons (about 1.66 × 10 ⁻²⁰ g to about 8.30 × 10 ⁻¹⁹ g). The article of claim 13,
The copolymer comprises the following repeating units:

In this case,
R ⁵ is an alkyl group having 1 to 12 carbon atoms,
R ⁶ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
n is an integer of 2 to 100,
x, y and z are the same or different and are independently integers of 10 to 5000,
Goods. The article of claim 13,
One or more biologically active molecules covalently bonded to the comonomer unit of the polyethylene oxide substituted methacrylate,
Further comprising an article. The article of claim 21,
The copolymer comprises the following repeating units:

In this case,
R ⁷ is a hydrogen atom or an alkyl group of 1 to 6 carbons,
n is an integer of 2 to 100,
x, y and z are the same or different and are each independently an integer from 10 to 2500;
Goods. The article of claim 13,
An article that is a medical device or a part of a medical device.